Organic compounds

ABSTRACT

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D1/D2 receptor signaling systems, and/or the treatment of residual symptoms.

This international application claims priority to U.S. ProvisionalApplication No. 61/975,502 filed on Apr. 4, 2014, and U.S. ProvisionalApplication No. 62/015,120, filed on Jun. 20, 2014, the contents of eachof which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to particular substituted heterocycle fusedgamma-carbolines, in free, pharmaceutically acceptable salt and/orsubstantially pure form as described herein, pharmaceutical compositionsthereof, and methods of use in the treatment of diseases involving5-HT_(2A) receptor, serotonin transporter (SERT) and/or pathwaysinvolving dopamine D₁/D₂ receptor signaling systems, e.g., diseases ordisorders such as anxiety, psychosis, schizophrenia, sleep disorders,sexual disorders, migraine, conditions associated with cephalic pain,social phobias, gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility and obesity; depression and mooddisorders associated with psychosis or Parkinson's disease; psychosissuch as schizophrenia associated with depression; bipolar disorder; andother psychiatric and neurological conditions, as well as tocombinations with other agents.

Psychosis, particularly schizophrenia, affects 1.1% of the populationworldwide. This illness comprises three phases: prodromal phase, activephase and residual phase. Prodromal phase is an early phase whereinsubclinical signs and symptoms are observed. These symptoms may includeloss of interest in usual pursuits, withdrawal from friends and familymembers, confusion, trouble with concentration, feeling of listlessnessand apathy. Active phase is characterized by exacerbations of positivesymptoms such as delusions, hallucinations and suspiciousness. Residualphase is characterized by negative symptoms such as emotionalwithdrawal, passive social withdrawal, and stereotyped thinking; andgeneral psychopathology symptoms including active social avoidance,anxiety, tension, and somatic concerns. Residual phase symptoms also areoften accompanied by depression, cognitive dysfunction and insomnia.Collectively, these residual phase symptoms are not well-treated by manyantipsychotic drugs currently available on the market and therefore areusually observed after the active phase symptoms have subsided aftertreatment. This phase of the illness is when patients would like toreturn to more productive and fulfilling lives, but since the residualnegative symptoms and cognitive impairment are not properly treated, itfrustrates the return to such a function. There remains an urgent needfor anti-psychotic agent, which can treat not just the active or acutephase symptoms, but also the residual phase symptoms of psychosis, e.g.,schizophrenia. In addition, there is a need for medications to treatthese symptoms that are free from undesirable side effects caused byoff-target interactions with histamine H1 and muscarinic acetylcholinereceptor systems.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT2 receptors, particularly 5-HT_(2A) and 5-HT_(2C)receptors, in treating central nervous system disorders. These compoundshave been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, as novel compoundsuseful for the treatment of disorders associated with 5-HT_(2A) receptormodulation such as obesity, anxiety, depression, psychosis,schizophrenia, sleep disorders, sexual disorders migraine, conditionsassociated with cephalic pain, social phobias, gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility,and obesity.

PCT/US08/03340 (WO 2008/112280) and U.S. application Ser. No. 10/786,935disclose methods of making substituted heterocycle fusedgamma-carbolines and uses of these gamma-carbolines as serotoninagonists and antagonists useful for the control and prevention ofcentral nervous system disorders such as addictive behavior and sleepdisorders.

WO/2009/145900 discloses use of particular substituted heterocycle fusedgamma-carbolines for the treatment of a combination of psychosis anddepressive disorders as well as sleep, depressive and/or mood disordersin patients with psychosis or Parkinson's disease. In addition todisorders associated with psychosis and/or depression, this patentapplication discloses and claims use of these compounds at a low dose toselectively antagonize 5-HT_(2A) receptors without affecting orminimally affecting dopamine D₂ receptors, thereby useful for thetreatment of sleep disorders without the side effects of the dopamine D₂pathways or side effects of other pathways (e.g., GABA_(A) receptors)associated with conventional sedative-hypnotic agents (e.g.,benzodiazepines) including but not limited to the development of drugdependency, muscle hypotonia, weakness, headache, blurred vision,vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pains,and chest pains.

Furthermore, it has been discovered that these substituted heterocyclefused gamma-carboline compounds are effective in treating not just acutesymptoms, but also residual symptoms of psychosis. Therefore, methods ofusing these substituted heterocycle fused gamma-carboline compounds,either alone or as an adjunctive therapy for the treatment of residualsymptoms of psychosis, particularly schizophrenia, were disclosed. Seefor example, application PCT/US2014/68443.

WO 2009/114181 discloses methods of preparing toluenesulfonic acidaddition salt crystals of particular substituted heterocycle fusedgamma-carbolines, e.g., toluenesulfonic acid addition salt of4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

WO 2011/133224 discloses prodrugs/metabolites of substituted heterocyclefused gamma-carboline for improved formulation, e.g.,extended/controlled release formulation. This application discloses thatheterocycle fused gamma-carboline N-substituted with a4-fluorophenyl(4-hydroxy)butyl moiety are shown to have high selectivityfor the serotonin transporter (SERT) relative to the heterocycle fusedgamma-carboline containing 4-fluorophenylbutanone. The hydroxy group onthese compounds, however, is inter-converted to and from the ketonewithin the plasma and the brain, allowing it to serve as a reservoir forthe 4-fluorophenylbutanone drug. While substituted heterocycle fusedgamma-carbolines and their uses are known, our inventors havesurprisingly found that particular substituted heterocycle fusedgamma-carbolines, while less active in in-vitro tests, areinter-converted between these less active compounds and the highlyactive ketone drug within the plasma and the brain. Our inventors havefurther provided prodrugs of particular substituted heterocycle fusedgamma-carbolines that have altered pharmacokinetic profile, e.g.,altered mechanisms and/or rate of absorption and distribution, andtherefore may be useful for an improved formulation and/or forcontrolling the duration of the effect of the drug in the body (e.g.,for sustained- or controlled release).

WO 2013/155505 discloses compounds which block the in vivointer-conversion between the hydroxy and the ketone, by incorporating analkyl substituent on the carbon bearing the hydroxyl group, thusyielding compounds which antagonize 5-HT_(2A) receptors and also inhibitserotonin re-uptake transporter.

Some of the major routes of metabolism of the previously disclosedketone and ether compounds are N-demethylation and O-demethylationcatalyzed by cytochrome oxidase enzymes, and ketone reduction catalyzedby ketone reductase.

SUMMARY OF THE INVENTION

Without being bound by theory, the current invention provides compoundswhich partially limit metabolism of the N-methyl substituent, byincorporating deuterium atoms in various locations. Drug compounds inwhich deuterium is substituted for hydrogen are believed to generallyhave similar biological activity to the non-deuterated analog. Thus, thecurrent invention provides compounds containing a mono-, di- ortri-deuterated N-methyl, or a mono- or di-deuterated methylene adjacentto the N-methyl, or any combination of these deuterium substitutions.The current invention also provides 0-deuteroalkyl ether analogs of thepreviously disclosed alcohols, which will also limit metabolism of theO-alkyl substituent. These novel compounds will antagonize 5-HT_(2A)receptors, inhibit the serotonin re-uptake transporter, and modulatedopamine receptor initiated protein phosphorylation, in a like manner asto their natural hydrogen analogs, but will have an improved metabolicprofile. Our inventors have shown that deuterations of somemetabolically labile positions improves in vitro hepatic microsomestability, whereas deuteration of the 4-fluorophenyl ring (to yield acompound containing a 2,3,5,6-tetradeutero-4-fluoro ring) does notimprove microsomal stability.

The current invention also provides further compounds which partially orfully block the in vivo inter-conversion between the hydroxy and theketone, by way of incorporating a deuterium atom at the carbon bearingthe hydroxyl group, yielding new, novel compounds which antagonize5-HT_(2A) receptors, inhibit the serotonin re-uptake transporter, andmodulate dopamine receptor initiated protein phosphorylation.

In the first aspect, the invention provides a compound of formula I:

wherein:

X is N(H), N(R⁵) or O;

R⁵ is C₁₋₆ alkyl, optionally substituted with D (e.g. CH₃, CH₂D, CHD₂ orCD₃);

R³ and R⁴ are each independently H or D;

R⁶ is H or D;

R¹ is H, or

-   -   C₁₋₆ alkyl, optionally substituted with D (e.g. CH₃, CH₂D, CHD₂        or CD₃), or a pharmaceutically acceptable and physiologically        labile moiety, e.g. a pharmaceutically acceptable and        physiologically labile acyl moiety, for example, wherein the        labile moiety is —C(O)—R², and R² is a C₁₋₂₁ alkyl, e.g., a        linear C₁₋₂₁ alkyl,    -   wherein D is deuterium,

and provided that at least one of R¹, R², R³, R⁴, R⁵, or R⁶ includes atleast one D; in free or salt form.

In a second aspect, the invention provides the Compound of Formula I-B:

wherein:

X is N(H), N(R⁵) or O;

R⁵ is C₁₋₆ alkyl;

R¹ is H, or

-   -   C₁₋₆ alkyl, or    -   a pharmaceutically acceptable and physiologically labile moiety,        e.g. a pharmaceutically acceptable and physiologically labile        acyl moiety, for example, wherein the labile moiety is —C(O)—R²,        and R² is a C₁₋₂₁ alkyl, e.g., a linear C₁₋₂₁ alkyl,

and wherein D is deuterium;

In a further embodiment, the invention provides the Compound of FormulaI or I-B, as described in the following formulae:

-   -   1.1 the compound of Formula I or I-B, wherein R¹ is H;    -   1.2 the compound of Formula I or I-B, wherein R¹ is C₁₋₆alkyl        (e.g., methyl);    -   1.3 the compound of Formula I or I-B, wherein R¹ is C₁₋₆ alkyl        optionally substituted with D;    -   1.4 the compound of Formula I or I-B, wherein R¹ is CH₃;    -   1.5 the compound of Formula I or I-B wherein R¹ is CD₃;    -   1.6 the compound of Formula I or I-B, wherein R¹ is a        pharmaceutically acceptable and physiologically labile moiety,        e.g. a pharmaceutically acceptable and physiologically labile        acyl moiety;    -   1.7 the compound of Formula I or I-B, wherein R1 is —C(O)—R²,        and wherein R² is C₁₋₂₁ alkyl;    -   1.8 the compound of Formula I or I-B, wherein R1 is —C(O)—R²,        and wherein R² is C₁₋₁₅ alkyl;    -   1.9 the compound of Formula I or I-B, wherein R1 is —C(O)—R²,        and wherein R² is C₁₋₉ alkyl;    -   1.10 the compound of Formula I or I-B, wherein R1 is —C(O)—R²,        and wherein R² is methyl, ethyl or propyl;    -   1.11 the compound of Formula I or I-B, wherein R1 is —C(O)—R²,        and wherein R² is methyl;    -   1.12 the compound of Formula I or I-B or any of formulae        1.1-1.11 wherein X is N(H), N(R⁵) or O;    -   1.13 the compound of Formula I or I-B or any of formulae        1.1-1.11, wherein X is O;    -   1.14 the compound of Formula I or I-B or any of formulae        1.1-1.11, wherein X is N(H);    -   1.15 the compound of Formula I or I-B or any of formulae        1.1-1.11, wherein X is N(R⁵), and wherein R⁵ is C₁₋₄ alkyl;    -   1.16 the compound of Formula I or I-B or any of formulae        1.1-1.11, wherein X is N(R⁵), and wherein R⁵ is CH₃;    -   1.17 the compound of Formula I or I-B or any of formulae        1.1-1.11, wherein X is N(R⁵), and wherein R⁵ is CD₃;    -   1.18 the compound of Formula I or I-B or any of formula        1.1-1.17, wherein R³ is D;    -   1.19 the compound of Formula I or I-B or any of formula        1.1-1.17, wherein R⁴ is D;    -   1.20 the compound of Formula I or I-B or any of formula        1.1-1.17, wherein R³ and R⁴ are D;    -   1.21 the compound of Formula I or I-B or any of formula        1.1-1.20, wherein X is N(R⁵), and R⁵ is CD₃ and R³ and R⁴ are        both D;    -   1.22 the Compound of Formula I or I-B or any of formulae        1.1-1.21, wherein the Compound is:

-   -   1.23 the Compound of Formula I or I-B or any of 1.1-1.21,        wherein the Compound is:

-   -   1.24 the Compound of Formula I or I-B or any of 1.1-1.21,        wherein the Compound is:

-   -   1.25 the Compound of Formula I or I-B or any of 1-1.21, wherein        the Compound is in substantially pure diastereomeric form (i.e.,        substantially free from other diastereomers);    -   1.26 the Compound of Formula I or I-B or any of 1-1.21, wherein        the Compound has a diastereomeric excess of greater than 70%,        preferably greater than 80%, more preferably greater than 90%        and most preferably greater than 95%;        in free or salt form.

In a further embodiment of the first or second aspect, the inventionprovides a compound of Formula I, in free or salt form as described inthe following formulae:

-   -   4.1 the Compound of Formula I or any of 1-1.26, wherein the salt        is selected from a group consisting of hydrochloric,        hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic,        propionic, succinic, glycolic, stearic, lactic, malic, tartaric,        citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic,        glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,        fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,        oxalic, isethionic, and the like;    -   4.2 the Compound of Formula I or I-B or formula 4.1, wherein the        salt is fumaric acid addition salt;    -   4.3 the Compound of Formula I or I-B or formula 4.1, wherein the        salt is phosphoric acid addition salt;    -   4.4 the Compound of Formula I or I-B or formula 4.1, wherein the        salt is a toluenesulfonic acid addition salt.

In a third aspect, the invention provides a pharmaceutical compositioncomprising the compound of formula I or I-B, or any of 1-1.26 or 4.1-4.4(the Compounds of the Invention), in free or pharmaceutically acceptablesalt form, in admixture with a pharmaceutically acceptable diluent orcarrier, e.g. to provide immediate release or to provide sustained ordelayed release.

In a further embodiment of the third aspect, the PharmaceuticalComposition of the Invention is for a sustained or delayed release,e.g., a depot formulation. In one embodiment, the depot formulationcomprises the Compounds of the Invention in a polymeric matrix. Inanother embodiment, the Compounds of the Invention are dispersed ordissolved within the polymeric matrix. In a further embodiment, thepolymeric matrix comprises standard polymers used in depot formulationssuch as polymers selected from a polyester of a hydroxy fatty acid andderivatives thereof, or a polymer of an alkyl alpha-cyanoacrylate, apolyalkylene oxalate, a poly(ortho ester), a polycarbonate, apolyortho-carbonate, a poly(amino acid), a hyaluronic acid ester, andmixtures thereof. In a further embodiment, the polymer is selected froma group consisting of polylactide, poly d,l-lactide, poly glycolide,PLGA 50:50, PLGA 75:25, PLGA 85:15 and PLGA 90:10 polymer. In anotherembodiment, the polymer is selected from poly(glycolic acid),poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing,poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,polydioxonone, poly(ortho carbonates), poly(acetals), poly(lacticacid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone),polyanhydrides, and natural polymers including albumin, casein, andwaxes, such as, glycerol mono- and distearate, and the like. In aparticular embodiment, the polymeric matrix comprises poly(d,l-lactide-co-glycolide). Any of the Compositions hereinbeforedescribed may be a pharmaceutical composition wherein said compositionis in admixture with a pharmaceutically acceptable diluent or carrier.

The (Pharmaceutical) depot formulations as hereinbefore described areparticularly useful for sustained or delayed release, wherein theCompounds of the Invention are released upon degradation of thepolymeric matrix. These Compositions may be formulated for controlled-and/or sustained-release of the Compounds of the Invention (e.g., as adepot composition) over a period of up to 180 days, e.g., from about 14to about 30 to about 180 days. For example, the polymeric matrix maydegrade and release the Compounds of the Invention over a period ofabout 30, about 60 or about 90 days. In another example, the polymericmatrix may degrade and release the Compounds of the Invention over aperiod of about 120, or about 180 days.

In still another further embodiment, the Pharmaceutical Compositions ofthe Invention, particularly the depot compositions of the Invention, areformulated for administration by injection.

In the fourth aspect, the invention provides the Compounds of theInvention as hereinbefore described in an oral sustained or delayedrelease formulation. For example, the invention provides an osmoticcontrolled release oral delivery system (OROS) for delivery of theCompounds of the Invention, e.g. analogous to the systems described inWO 2000/35419 and EP 1 539 115 (U.S. Pub. No. 2009/0202631), thecontents of each of which applications are incorporated by reference intheir entirety. Therefore in one embodiment of this aspect, theinvention provides a pharmaceutical composition or device comprising (a)a gelatin capsule containing a Compound of the Invention in free orpharmaceutically acceptable salt form or a Pharmaceutical Composition ofthe Invention, as hereinbefore described; (b) a multilayer wallsuperposed on the gelatin capsule comprising, in outward order from thecapsule: (i) a barrier layer, (ii) an expandable layer, and (iii) asemipermeable layer; and (c) and orifice formed or formable through thewall. (Composition P.1)

In another embodiment of this aspect, the invention provides acomposition comprising a gelatin capsule containing a liquid, theCompounds of the Invention in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention as hereinbeforedescribed, the gelatin capsule being surrounded by a composite wallcomprising a barrier layer contacting the external surface of thegelatin capsule, an expandable layer contacting the barrier layer, asemi-permeable layer encompassing the expandable layer, and an exitorifice formed or formable in the wall. (Composition P.2)

In still another embodiment of the fourth aspect, the invention providesa composition comprising a gelatin capsule containing a liquid, theCompound of the Invention in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention as hereinbeforedescribed, the gelatin capsule being surrounded by a composite wallcomprising a barrier layer contacting the external surface of thegelatin capsule, an expandable layer contacting the barrier layer, asemipermeable layer encompassing the expandable layer, and an exitorifice formed or formable in the wall, wherein the barrier layer formsa seal between the expandable layer and the environment at the exitorifice. (Composition P.3)

In still another embodiment of the fourth aspect, the invention providesa composition comprising a gelatin capsule containing a liquid, theCompound of the Invention in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention as hereinbeforedescribed, the gelatin capsule being surrounded by a barrier layercontacting the external surface of the gelatin capsule, an expandablelayer contacting a portion of the barrier layer, a semi-permeable layerencompassing at least the expandable layer, and an exit orifice formedor formable in the dosage form extending from the external surface ofthe gelatin capsule to the environment of use. (Composition P.4). Theexpandable layer may be formed in one or more discrete sections, such asfor example, two sections located on opposing sides or ends of thegelatin capsule.

In a particular embodiment of the fourth aspect, the Compound of theInventions in the Osmotic-controlled Release Oral delivery System (i.e.,in Composition P.1-P.4) are in a liquid formulation, which formulationmay be neat, liquid active agent, liquid active agent in a solution,suspension, emulsion or self-emulsifying composition or the like.

Further information on Osmotic-controlled Release Oral delivery Systemcomposition including characteristics of the gelatin capsule, barrierlayer, an expandable layer, a semi-permeable layer; and orifice may befound in WO 2000/35419, the contents of which are incorporated byreference in their entirety. Other Osmotic-controlled Release Oraldelivery System for the Compound or the Pharmaceutical Composition ofthe Invention may be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631),the contents of which are incorporated by reference in their entirety.

Therefore, in another embodiment of the fourth aspect, the inventionprovides a composition or device comprising (a) two or more layers, saidtwo or more layers comprising a first layer and a second layer, saidfirst layer comprises the Compound of the Invention, in free orpharmaceutically acceptable salt form, or a Pharmaceutical Compositionas herein before described said second layer comprises a polymer; (b) anouter wall surrounding said two or more layers; and (c) an orifice insaid outer wall. (Composition P.5)

Composition P.5 preferably utilizes a semi-permeable membranesurrounding a three-layer-core: in these embodiments the first layer isreferred to as a first drug layer and contains low amounts of drug(e.g., the Compounds of the Invention) and an osmotic agent such assalt, the middle layer referred to as the second drug layer containshigher amounts of drug, excipients and no salt; and the third layerreferred to as the push layer contains osmotic agents and no drug. Atleast one orifice is drilled through the membrane on the first druglayer end of the capsule-shaped tablet. (Composition P.6)

Composition P.5 or P.6 may comprise a membrane defining a compartment,the membrane surrounding an inner protective subcoat, at least one exitorifice formed or formable therein and at least a portion of themembrane being semi-permeable; an expandable layer located within thecompartment remote from the exit orifice and in fluid communication withthe semi-permeable portion of the membrane; a first drug layer locatedadjacent the exit orifice; and a second drug layer located within thecompartment between the first drug layer and the expandable layer, thedrug layers comprising the Compound of the Invention in free orpharmaceutically acceptable salt thereof. Depending upon the relativeviscosity of the first drug layer and second drug layer, differentrelease profiles are obtained. It is imperative to identify the optimumviscosity for each layer. In the present invention, viscosity ismodulated by addition of salt, sodium chloride. The delivery profilefrom the core is dependent on the weight, formulation and thickness ofeach of the drug layers. (Composition P.7)

In a particular embodiment, the invention provides Composition P.7wherein the first drug layer comprising salt and the second drug layercontaining no salt. Composition P.5-P.7 may optionally comprise aflow-promoting layer between the membrane and the drug layers.Compositions P.1-P.7 will generally be referred to as Osmotic-controlledRelease Oral delivery System Composition.

In the fifth aspect, the invention provides a method (Method I) for thetreatment or prophylaxis of a central nervous system disorder,comprising administering to a patient in need thereof, a Compound ofFormula I or I-B or any of formulae 1-1.26, in free or pharmaceuticallyacceptable salt form as described in any of 4.1-4.4, or a pharmaceuticalcomposition as hereinbefore described.

In a further embodiment of the fifth aspect, the invention providesMethod I wherein the method is further as described in the followingformulae:

-   -   7.1 Method I, wherein the central nervous system disorder is one        or more disorders associated with dementia, e.g., disorders        associated with mild cognition impairment and dementing        illnesses including senile dementia, Alzheimer's disease, Pick's        disease, fronto-temporal dementia, parasupranuclear palsy,        dementia with Lewy bodies, vascular dementia, Huntington's        disease, Parkinson's disease, multiple sclerosis, amyotrophic        lateral sclerosis, Down syndrome, elderly depression,        Wernicke-Korsakoffs syndrome, cortico-basal degenerations and        prion disease, autism and attention deficit hyperactivity        disorder, as disclosed in WO 2013/155506, the contents of which        is incorporated herein by reference in its entirety;    -   7.2 Method I or 7.1, wherein the disorders associated with        dementia is selected from the group consisting of (1) behavioral        or mood disorders such as agitation/irritation,        aggressive/assaultive behavior, anger, physical or emotional        outbursts; (2) psychosis; (3) depression; and (4) sleep        disorders;    -   7.3 Method I or 7.1, wherein the central nervous system disorder        is agitation/irritation, aggressive/assaultive behavior, anger,        physical or emotional outbursts as disclosed in WO 2013/155504,        the contents of which is incorporated herein by reference in its        entirety;    -   7.4 Method I, wherein the central nervous system disorder is a        disorder selected from a group consisting of obesity, anxiety,        depression (for example refractory depression and major        depressive disorder (MDD)), psychosis, schizophrenia, sleep        disorders (particularly sleep disorders associated with        schizophrenia and other psychiatric and neurological diseases),        sexual disorders, migraine, conditions associated with cephalic        pain, social phobias, agitation in dementia (e.g., agitation in        Alzheimer's disease), agitation in autism and related autistic        disorders, and gastrointestinal disorders such as dysfunction of        the gastrointestinal tract motility;    -   7.5 Method I or any of 7.1-7.4, wherein the central nervous        system disorder is a disorder involving serotonin 5-HT_(2A),        dopamine D₁/D₂ receptor system and/or serotonin reuptake        transporter (SERT) pathways as similarly described in        WO/2009/145900, the contents of which are herein incorporated by        reference in their entirety;    -   7.6 Method I or any of Formulae 7.1-7.5, wherein the central        nervous system disorder is a disorder involving serotonin        reuptake transporter (SERT) pathways;    -   7.7 Method I or any of Formulae 7.1-7.6, wherein the central        nervous system disorder is a disorder selected from the        following: (i) psychosis, e.g., schizophrenia, in a patient        suffering from depression; (2) depression in a patient suffering        from psychosis, e.g., schizophrenia; (3) mood disorders        associated with psychosis, e.g., schizophrenia or Parkinson's        disease; and (4) sleep disorders associated with psychosis,        e.g., schizophrenia or Parkinson's disease; (5) depression; (6)        anxiety; (7) post-traumatic stress disorder; or (8) impulse        control disorder, e.g., intermittent explosive disorder;    -   7.8 Method I or any of Formulae 7.1-7.7, wherein the central        nervous system disorder is psychosis, e.g., schizophrenia and        said patient is a patient suffering from depression;    -   7.9 Method I or any of Formulae 7.1-7.8, wherein said patient is        unable to tolerate the side effects of convention antipsychotic        drugs, e.g., chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine, molindone, perphenazine,        pimozide, prochlorperazine, promazine, thioridazine,        thiothixene, trifluoperazine, clozapine, aripiprazole,        olanzapine, quetiapine, risperidone and ziprasidone;    -   7.10 Method I or any of Formulae 7.1-7.9, wherein said patient        is unable to tolerate the side effects of convention        antipsychotic drugs, e.g., haloperidol, aripiprazole, clozapine,        olanzapine, quetiapine, risperidone, and ziprasidone;    -   7.11 Method I or any of Formulae 7.1-7.10, wherein said disorder        is depression and said patient is a patient suffering from        psychosis, e.g., schizophrenia, or Parkinson's disease;    -   7.12 Method I or any of Formulae 7.1-7.6, wherein said disorder        is sleep disorder and said patient is suffering from depression;    -   7.13 Method I or any of 7.1-7.6, wherein said one or more        disorders is sleep disorder and said patient is suffering from        psychosis, e.g., schizophrenia;    -   7.14 Method I or any of 7.1-7.6, wherein said one or more        disorders is sleep disorder and said patient is suffering from        Parkinson's disease;    -   7.15 Method I or any of 7.1-7.6, wherein said one or more        disorders is sleep disorder and said patient is suffering from        depression and psychosis, e.g., schizophrenia, or Parkinson's        disease;    -   7.16 Method I or any of 7.1-7.6, wherein the central nervous        system disorder is residual symptoms of psychosis, for example,        schizophrenia (e.g., residual sub-type), delusional disorder        (e.g., somatic type), major depression with psychosis, bipolar        disorder with psychotic symptoms, brief psychotic disorder,        schizophreniform disorder, schizoaffective disorder or psychosis        caused by a medical condition or substance use. Preferably, the        patient is suffering from residual symptoms of schizophrenia;    -   7.17 Method I or any of 7.1-7.6, wherein the residual phase        symptoms include: negative symptoms such as blunted affect,        emotional withdrawal, poor rapport, passive or apathetic social        withdrawal, difficulty in abstract thinking, lack of spontaneity        and flow of conversation and stereotyped thinking; general        psychopathology symptoms such as somatic concern, anxiety, guilt        feelings, tension, mannerisms and posturing, depression, motor        retardation, uncooperativeness, unusual thought content,        disorientation, poor attention, lack of judgment and insight,        disturbance of volition, poor impulse control, preoccupation and        active social avoidance; cognitive impairment and sleep        disorders (e.g., insomnia);    -   7.18 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, preferably 2.5 mg-50 mg, still preferably 1-40        mg, e.g., 1-10 mg, e.g., 10 mg, 20 mg, greater 20 mg, e.g., 30        mg, 40 mg;    -   7.19 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day, still        preferably 1-40 mg/day, e.g., 1-10 mg/day, e.g., 10 mg/day, 20        mg/day, greater 20 mg/day, e.g., 30 mg/day, 40 mg/day;    -   7.20 Any of the foregoing methods wherein a condition to be        treated is dyskinesia, e.g. in a patient receiving dopaminergic        medications, e.g., medications selected from levodopa and        levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B        inhibitors), dopamine agonists, and anticholinergics, e.g.,        levodopa;    -   7.21 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease;    -   7.22 Any of the foregoing methods wherein the patient does not        respond to a selective serotonin re-uptake inhibitor, e.g.        selected from one or more of citalopram (Celexa, Cipramil,        Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox,        Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex,        Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex,        Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox        (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine        (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine        (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,        Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine,        Deparoc); sertraline (Zoloft, Lustral, Serlain, Asentra);        vilazodone (Viibryd); or zimelidine (Zelmid, Normud);    -   7.23 Any of the foregoing methods wherein the patients is also        receiving a selective serotonin re-uptake inhibitor, e.g.        selected from one or more of citalopram (Celexa, Cipramil,        Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox,        Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex,        Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex,        Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox        (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine        (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine        (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,        Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine,        Deparoc); sertraline (Zoloft, Lustral, Serlain, Asentra);        vilazodone (Viibryd); or zimelidine (Zelmid, Normud);    -   7.24 Any of the foregoing methods wherein the patients is        suffering from autistic spectrum disorder, e.g., autism or        Asperger Syndrome;    -   7.25 Any of the foregoing methods wherein the patients is        suffering from dementia, e.g., disorders associated with mild        cognition impairment and dementing illnesses including senile        dementia, Alzheimer's disease, Pick's disease, fronto-temporal        dementia, parasupranuclear palsy, dementia with Lewy bodies,        vascular dementia, Huntington's disease, Parkinson's disease,        multiple sclerosis, amyotrophic lateral sclerosis, Down        syndrome, elderly depression, Wernicke-Korsakoff s syndrome,        cortico-basal degenerations and prion disease, autism and        attention deficit hyperactivity disorder;    -   7.26 Any of the foregoing methods wherein the patient is also        receiving a cholinesterase inhibitor (e.g., acetylcholinesterase        inhibitor) or an N-Methyl D-Aspartate (NMDA) receptor        antagonist, in free or pharmaceutically acceptable salt form;    -   7.27 Method 7.26, wherein the cholinesterase inhibitor (e.g.,        acetylcholinesterase inhibitor) is selected from the group        consisting of Tacrine, rivastigmine (Exelon), donepezil        (Aricept), and galantamine (Razadyne, formerly called Reminyl))        in free or pharmaceutically acceptable salt form;    -   7.28 Method 7.26, wherein the cholinesterase inhibitor (e.g.,        acetylcholinesterase inhibitor) is donepezil in free or        pharmaceutically acceptable salt form;    -   7.29 Method 7.26, wherein the NMDA receptor antagonist is        memantine in free or pharmaceutically acceptable salt form;    -   7.30 Any of the foregoing methods further comprising        administering one or more other therapeutic agents such as        additional antipsychotic agents and/or anti-depressive agents        and/or hypnotic agents;    -   7.31 Method 7.30, wherein the one or more other therapeutic        agents are selected from anti-depressive agents such as        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission), a GABA-B agonist, a        5-HT modulator (e.g., a 5-HTiA agonist, a 5-HT_(2A) antagonist,        a 5-HT_(2A) inverse agonist, etc.), a melatonin agonist, an ion        channel modulator (e.g., blocker), a serotonin-2        antagonist/reuptake inhibitor (SARIs), an orexin receptor        antagonist, an H3 agonist, a noradrenergic antagonist, a galanin        agonist, a CRH antagonist, human growth hormone, a growth        hormone agonist, estrogen, an estrogen agonist, a neurokinin-1        drug; and antipsychotic agents, e.g., atypical antipsychotic        agents, in free or pharmaceutically acceptable salt form;    -   7.32 Method 7.30 or 7.31, wherein the one or more other        therapeutic agents are antipsychotic agents, e.g.,        chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine,        mesoridazine, molindone, perphenazine, pimozide,        prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone, ziprasidone, paliperidone, asenapine,        lurasidone, iloperidone, cariprazine, amisulpride, zotepine,        sertindole, wherein the one or more other therapeutic agents are        administered as an adjunct to the compound of Formula I or the        compound of Formula I is an adjunct to the one or more other        therapeutic agents.

In a particular embodiment of the fifth aspect, the invention provides amethod (Method I_(P)) for the treatment or prophylaxis of a centralnervous system disorder as hereinbefore described, comprisingadministering to a patient in need thereof:

-   -   7.4P a compound of Formula I or I-B or any of formulae 1-1.26,        in free or (pharmaceutically acceptable) salt form as described        in any of 4.1-4.4;    -   7.8P a Pharmaceutical or Depot Composition as hereinbefore        described; or    -   7.11P Osmotic-controlled Release Oral delivery System        Composition as hereinbefore described.

In a further embodiment of the fifth aspect, the invention providesMethod I_(P), wherein the method is further described in any one offormulae 7.1-7.32.

In a particular embodiment of the fifth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder isschizophrenia or sleep disorder.

In a particular embodiment of the fifth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder is depressionor anxiety.

In a particular embodiment of the fifth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder ispost-traumatic stress disorder or an impulse control disorder, e.g.,intermittent explosive disorder.

In a particular embodiment of the fifth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder ispost-traumatic stress disorder or an impulse control disorder, e.g.,intermittent explosive disorder in a patient suffering from dementia,e.g., senile dementia, Alzheimer's disease, Pick's disease,fronto-temporal dementia, parasupranuclear palsy, dementia with Lewybodies, vascular dementia, Huntington's disease, Parkinson's disease,multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome,elderly depression, Wernicke-Korsakoffs syndrome, cortico-basaldegenerations, prion disease, autism and/or attention deficithyperactivity disorder.

In still another embodiment of the fifth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the Depot Composition ofthe Invention is administered for controlled- and/or sustained-releaseof the Compounds of the Invention over a period of from about 14 days,about 30 to about 180 days, preferably over the period of about 30,about 60 or about 90 days. Controlled- and/or sustained-release isparticularly useful for circumventing premature discontinuation oftherapy, particularly for antipsychotic drug therapy wherenon-compliance or non-adherence to medication regimes is a commonoccurrence.

In the sixth aspect, the invention provides a method (Method II) for theprophylaxis or treatment one or more sleep disorders, agitation,aggressive behaviors, post-traumatic stress disorder and/or impulsecontrol disorder, e.g., intermittent explosive disorder, comprisingadministering to a patient in need thereof a compound as described inthe following formulae:

-   -   8.1 a compound of Formula I or I-B or any of formulae 1-1.26, in        free or (pharmaceutically acceptable) salt form as described in        any of 4.1-4.4;    -   8.2 a Pharmaceutical or Depot Composition as hereinbefore        described;    -   8.3 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described.

In one embodiment of the sixth aspect, the invention provides Method IIor any of 8.1-8.3, wherein the disorder is sleep disorders. In anotherembodiment of the fifth aspect, the invention provides Method II,wherein the disorder is agitation, aggressive behaviors, post-traumaticstress disorder and/or impulse control disorder, e.g., intermittentexplosive disorder.

In a further embodiment of the sixth aspect, the invention providesMethod II, 8.1-8.3, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed;

-   -   8.11 Any of the foregoing methods, wherein the sleep disorder is        sleep maintenance insomnia;    -   8.12 Any of the foregoing methods, wherein the effective amount        is 1 mg-10 mg per day, e.g., 1-5 mg, preferably 2.5-5 mg, per        day, still preferably 10 mg per day;    -   8.13 Any of the foregoing methods, wherein the effective amount        is 2.5 mg or 5 mg, per day or 10 mg per day;    -   8.14 Any of the foregoing methods wherein the sleep disorder is        in a patient suffering from or at risk of dyskinesia, e.g., a        patient receiving dopaminergic medications, e.g., selected from        levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,        MAO-B inhibitors), dopamine agonists, and anticholinergics,        e.g., receiving levodopa;    -   8.15 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

The Compounds of the Invention provide effective treatment of 5-HT_(2A),SERT and/or D₂ receptor related disorders without or with minimalextrapyramidal side effects as similarly disclosed and claimed in WO2009/145900, the contents of which are incorporated by reference intheir entirety. Therefore, the Compounds of the Invention, thePharmaceutical Compositions of the Invention or the Depot Compositionsof the Invention may be used in combination with a second therapeuticagent, particularly at lower dosages than when the individual agents areused as a monotherapy so as to enhance the therapeutic activities of thecombined agents without causing the undesirable side effects commonlyoccur in conventional monotherapy. Therefore, the Compounds of theInvention may be simultaneously, sequentially, or contemporaneouslyadministered with other anti-depressant, anti-psychotic, other hypnoticagents, and/or agents use to treat Parkinson's disease or mood disordersor dementia. In another example, side effects may be reduced orminimized by administering a Compound of the Invention in combinationwith one or more second therapeutic agents in free or salt form, whereinthe dosages of (i) the second therapeutic agent(s) or (ii) both Compoundof the Invention and the second therapeutic agent, are lower than if theagent/compound are administered as a monotherapy. In a particularembodiment, the Compounds of the Invention are useful to treatdyskinesia in a patient receiving dopaminergic medications, e.g.,selected from levodopa and levodopa adjuncts (carbidopa, COMTinhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics,e.g., such as are used in the treatment of Parkinson's disease.

Therefore, in the seventh aspect, the current invention provides MethodI or I_(P), e.g., or any of formulae 7.1-7.32, or Method II or any of8.1-8.15, further comprises one or more therapeutic agents selected fromcompounds that modulate GABA activity (e.g., enhances the activity andfacilitates GABA transmission), a GABA-B agonist, a 5-HT modulator(e.g., a 5-HT_(1A) agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverseagonist, etc.), a melatonin agonist, an ion channel modulator (e.g.,blocker), a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexinreceptor antagonist, an H3 agonist or antagonist, a noradrenergicagonist or antagonist, a galanin agonist, a CRH antagonist, human growthhormone, a growth hormone agonist, estrogen, an estrogen agonist, aneurokinin-1 drug, an anti-depressant, and an antipsychotic agent, e.g.,an atypical antipsychotic agent, in free or pharmaceutically acceptablesalt form (Method I-A and II-A respectively).

In another embodiment of the seventh aspect, Method I-A and II-A, MethodI, Method I_(P), e.g., or any of formulae 7.1-7.32, or Method II or anyof 8.1-8.15, further comprises one or more therapeutic agents selectedfrom a cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor)or an N-Methyl D-Aspartate (NMDA) receptor antagonist, in free orpharmaceutically acceptable salt form. In a specific embodiment, thecholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) isselected from the group consisting of Tacrine, rivastigmine (Exelon),donepezil (Aricept), and galantamine (Razadyne, formerly calledReminyl)) in free or pharmaceutically acceptable salt form. In a furtherembodiment, the cholinesterase inhibitor (e.g., acetylcholinesteraseinhibitor) is donepezil in free or pharmaceutically acceptable saltform. In another embodiment, the NMDA receptor antagonist is memantinein free or pharmaceutically acceptable salt form.

In a further embodiment of the seventh aspect, the invention providesMethod I-A or II-A as follows, further comprising one or moretherapeutic agents.

-   -   9.1 Method I-A or II-A, wherein the therapeutic agent(s) is        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission);    -   9.2 Method I-A or II-A or 9.1, wherein the GABA compound is        selected from a group consisting of one or more of doxepin,        alprazolam, bromazepam, clobazam, clonazepam, clorazepate,        diazepam, flunitrazepam, fiurazepam, lorazepam, midazolam,        nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;    -   9.3 Method I-A or II-A, wherein the therapeutic agent is an        additional 5HT_(2A) antagonist;    -   9.4 Method I-A or II-A or 9.3, wherein said additional 5HT_(2A)        antagonist is selected from one or more of ketanserin,        risperidone, eplivanserin, volinanserin (Sanofi-Aventis,        France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY        10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego,        Calif.), and AVE8488 (Sanofi-Aventis, France); Method I-A or        II-A, 9.3 or 9.4 additionally selected from pimavanserin        (ACP-103) and pizotifen;    -   9.5 Method I-A or II-A, wherein the therapeutic agent is a        melatonin agonist;    -   9.6 Method I-A or II-A or 9.5, wherein the melatonin agonist is        selected from a group consisting of one or more of melatonin,        ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162        (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II        Discovery) and agomelatine;    -   9.7 Method I-A or II-A, wherein the therapeutic agent is an ion        channel blocker;    -   9.8 Method I-A or II-A or 9.7, wherein said ion channel blocker        is one or more of lamotrigine, gabapentin and pregabalin.    -   9.9 Method I-A or II-A, wherein the therapeutic agent is an        orexin receptor antagonist;    -   9.10 Method I-A or II-A or 9.9, wherein the orexin receptor        antagonist is selected from a group consisting of orexin, a        1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868        (GlaxoSmithKline) and a benzamide derivative;    -   9.11 Method I-A or II-A, wherein the therapeutic agent is the        serotonin-2 antagonist/reuptake inhibitor (SARI);    -   9.12 Method I-A or II-A or 9.11, wherein the serotonin-2        antagonist/reuptake inhibitor (SARI) is selected from a group        consisting of one or more Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone and trazodone;    -   9.13 Method I-A or II-A, wherein the therapeutic agent is the        5HT1a agonist;    -   9.14 Method I-A or II-A or 9.13, wherein the 5HT_(1a) agonist is        selected from a group consisting of one or more of repinotan,        sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San        Diego, Calif.);    -   9.15 Method I-A or II-A, wherein the therapeutic agent is the        neurokinin-1 drug;    -   9.16 Method I-A or II-A or 9.15, wherein the neurokinin-1 drug        is Casopitant (GlaxoSmithKline);    -   9.17 Method I-A or II-A, wherein the therapeutic agent is an        antipsychotic agent;    -   9.18 Method I-A or II-A or 9.17, wherein the antipsychotic agent        is selected from a group consisting of chlorpromazine,        haloperidol, droperidol, fluphenazine, loxapine, mesoridazine,        molindone, perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, clozapine,        aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone        and paliperidone;    -   9.19 Method I-A or II-A, wherein the therapeutic agent is an        anti-depressant;    -   9.20 Method I-A or II-A or 9.19, wherein the anti-depressant is        selected from amitriptyline, amoxapine, bupropion, citalopram,        clomipramine, desipramine, doxepin, duloxetine, escitalopram,        fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,        mirtazapine, nefazodone, nortriptyline, paroxetine, phenelazine        sulfate, protriptyline, sertraline, tranylcypromine, trazodone,        trimipramine, and venlafaxine;    -   9.21 Method I-A or II-A, 9.17 or 9.18, wherein the antipsychotic        agent is an atypical antipsychotic agent;    -   9.22 Method I-A or II-A, or any of 9.17-9.21, wherein the        atypical antipsychotic agent is selected from a group consisting        of clozapine, aripiprazole, olanzapine, quetiapine, risperidone,        ziprasidone, and paliperidone;    -   9.23 Method I-A or II-A, wherein the therapeutic agent is        selected from any of methods 9.1-9.22, e.g., selected from a        group consisting of modafinil, armodafinil, doxepin, alprazolam,        bromazepam, clobazam, clonazepam, clorazepate, diazepam,        flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,        oxazepam, temazapam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,        ketanserin, risperidone, eplivanserin, volinanserin        (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena        Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,        France), repinotan, sarizotan, eptapirone, buspirone, MN-305        (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,        Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,        Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,        lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a        benzamide derivative, Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone, trazodone, Casopitant        (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,        citalopram, clomipramine, desipramine, doxepin, duloxetine,        escitalopram, fluoxetine, fluvoxamine, imipramine,        isocarboxazid, maprotiline, mirtazapine, nefazodone,        nortriptyline, paroxetine, phenelazine sulfate, protriptyline,        sertraline, tranylcypromine, trazodone, trimipramine,        venlafaxine, chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine molindone, perphenazine,        pimozide, prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone, ziprasidone and paliperidone; In        addition to the therapeutic agents listed herewith, Method I-A        or II-A, is further selected from pimavanserin (ACP-103) and        pizotifen;    -   9.24 Method I-A or II-A wherein the therapeutic agent is an H3        agonist;    -   9.25 Method I-A or II-A, wherein the therapeutic agent is an H3        antagonist;    -   9.26 Method I-A or II-A, wherein the therapeutic agent is a        noradrenergic agonist or antagonist;    -   9.27 Method I-A or II-A, wherein the therapeutic agent is a        galanin agonist;    -   9.28 Method I-A or II-A, wherein the therapeutic agent is a CRH        antagonist;    -   9.29 Method I-A or II-A, wherein the therapeutic agent is a        human growth hormone;    -   9.30 Method I-A or II-A, wherein the therapeutic agent is a        growth hormone agonist;    -   9.31 Method I-A or II-A, wherein the therapeutic agent is        estrogen;    -   9.32 Method I-A or II-A, wherein the therapeutic agent is an        estrogen agonist;    -   9.33 Method I-A or II-A, wherein the therapeutic agent is a        neurokinin-1 drug;    -   9.34 Method I-A or II-A, wherein a therapeutic agent is combined        with compounds of Formula (I) and the therapeutic agent is an        anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,        stalova, Symmetrel, benzotropine, biperiden, bromocryiptine,        entacapone, pergolide, pramipexole, procyclidine, ropinirole,        selegiline and tolcapone;    -   9.35 Method I-A or II-A, wherein compounds of Formula I or I-B        may be used to treat sleep disorders, depression, psychosis, or        any combinations thereof, in patients suffering from the listed        diseases and/or Parkinson's disease;    -   9.36 Method I-A or II-A, wherein the disorder is selected from        at least one or more of psychosis, e.g., schizophrenia,        depression, mood disorders, sleep disorders (e.g., sleep        maintenance and/or sleep onset) or any combination of disorders        thereof;    -   9.37 Any of the foregoing methods wherein the disorder is sleep        disorder;    -   9.38 Any of the foregoing methods, wherein the disorder is sleep        disorder associated with psychosis, e.g., schizophrenia or        Parkinson's disease; in free or pharmaceutically acceptable salt        form.

In another embodiment of the seventh aspect, the current inventionprovides Method I_(P) or Method II as hereinbefore described, furthercomprises one or more therapeutic agents selected from compounds thatmodulate GABA activity (e.g., enhances the activity and facilitates GABAtransmission), a GABA-B agonist, a 5-HT modulator (e.g., a 5HT_(1A)agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist, etc.), amelatonin agonist, an ion channel modulator (e.g., blocker), aserotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptorantagonist, an H3 agonist or antagonist, a noradrenergic agonist orantagonist, a galanin agonist, a CRH antagonist, human growth hormone, agrowth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1drug, an anti-depressant, and an antipsychotic agent, e.g., an atypicalantipsychotic agent, in free or pharmaceutically acceptable salt form(Method I_(P)-A and II-A respectively). In a further embodiment of thisaspect, the invention provides Method I_(P)-A or II-A as similarlydescribed in any one of formulae 9.1-9.38.

In still another embodiment of the seventh aspect, Method I_(P) orMethod II as hereinbefore described further comprises one or moretherapeutic agents selected from a cholinesterase inhibitor (e.g.,acetylcholinesterase inhibitor) or an N-Methyl D-Aspartate (NMDA)receptor antagonist, in free or pharmaceutically acceptable salt form.In a specific embodiment, the cholinesterase inhibitor (e.g.,acetylcholinesterase inhibitor) is selected from the group consisting ofTacrine, rivastigmine (Exelon), donepezil (Aricept), and galantamine(Razadyne, formerly called Reminyl)) in free or pharmaceuticallyacceptable salt form. In a further embodiment, the cholinesteraseinhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in free orpharmaceutically acceptable salt form. In another embodiment, the NMDAreceptor antagonist is memantine in free or pharmaceutically acceptablesalt form.

In the eighth aspect of the invention, the combination of a Compound ofthe Invention and one or more second therapeutic agents as described inMethods I-A, II-A or any of 9.1-9.38, may be administered as aPharmaceutical Composition or a depot Composition as hereinbeforedescribed. Similarly, the combination of a Compound of the Invention andone or more second therapeutic agents as described in Methods I_(p)-A,II-A or any of 9.1-9.38, may be administered as a PharmaceuticalComposition or a depot Composition as hereinbefore described. Thecombination compositions can include mixtures of the combined drugs, aswell as two or more separate compositions of the drugs, which individualcompositions can be, for example, co-administered together to a patient.

In a particular embodiment, Methods I-A, II-A, I_(p)-A, II-A or any of9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with an atypical antipsychoticagent, e.g., a compound selected from clozapine, aripiprazole,olanzapine, quetiapine, risperidone, ziprasidone, or paliperidone, infree or pharmaceutically acceptable salt form, for example wherein thedosage of the atypical antipsychotic agent is reduced and/or sideeffects are reduced.

In another embodiment, Methods I-A, II-A, Methods I_(p)-A, II-A or anyof 9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with an anti-depressant, e.g.,amitriptyline, amoxapine, bupropion, citalopram, clomipramine,desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine,imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone,nortriptyline, paroxetine, phenelazine sulfate, protriptyline,sertraline, tranylcypromine, trazodone, trimipramine, or venlafaxine, infree or pharmaceutically acceptable salt form. Alternatively, theanti-depressant may be used as an adjunct medication in addition to thecompounds of the Invention.

In still another embodiment, Methods I-A, II-A, I_(p)-A, II-A or any of9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with a compound that modulatesGABA activity, e.g., a compound selected from doxepin, alprazolam,bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam,flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam,triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem,gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals),estazolam or any combinations thereof, in free or pharmaceuticallyacceptable salt form.

In another particular embodiment, Methods I-A, II-A, I_(p)-A, II-A orany of 9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with doxepin in free orpharmaceutically acceptable salt form. Dosages of doxepin can vary inany range known to a person of ordinary skill in the art. In oneexample, a 10 mg dose of doxepin may be combined with any dosage of acompound of the Invention.

In another embodiment, Methods I-A, II-A, I_(p)-A, II-A or any of9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination (including as part of a dailydosage regimen) with an atypical stimulant, e.g., a modafinil,adrafinil, or armodafinil. A regimen incorporating a Compound of theInvention with such drugs promotes more regular sleep, and avoids sideeffects such as psychosis or mania associated with higher levels of suchdrugs, e.g., in the treatment of bipolar depression, cognitionassociated with schizophrenia, and excessive sleepiness and fatigue inconditions such as Parkinson's disease and cancer.

In the ninth aspect, the invention provides use of a compound asdescribed in the following formulae:

-   -   11.1 Compound of Formula I or I-B or any of formulae 1-1.26, in        free or pharmaceutically acceptable salt form;    -   11.2 a Pharmaceutical Composition as hereinbefore described;    -   11.3 Depot Composition as hereinbefore described; or    -   11.4 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described,        (in the manufacture of a medicament) for the treatment or        prophylaxis of one or more disorders as disclosed hereinbefore,        e.g., in any of Method I, any of 7.1-7.32, Method II, any of        8.1-8.15, Methods I-A, II-A, any of 9.1-9.38, Method I_(P),        Methods Ip-A, or any methods described in the sixth or seventh        aspect of the invention.

In the tenth aspect, the invention provides a pharmaceutical compositionas hereinbefore described, e.g., in the following formulae:

-   -   12.1 a Pharmaceutical Composition as hereinbefore described;    -   12.2 Depot Composition as hereinbefore described; or    -   12.3 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described,        for use in the treatment or prophylaxis of one or more disorders        as disclosed hereinbefore, e.g., in any of Method I, any of        7.1-7.32, Method II, any of 8.1-8.15, Methods I-A, II-A, any of        9.1-9.38, Method I_(P), Methods Ip-A, or any methods described        in the sixth or seventh aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms asused herein have the following meetings:

-   -   a. “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, e.g., one to 21 carbon atoms, e.g., one to 6        carbon atoms in length, which may be linear or branched (e.g.,        n-butyl or tert-butyl), unless otherwise specified.    -   b. “Residual symptoms” as used herein include negative symptoms        and general psychopathology symptoms as described in the        Positive and Negative Symptom Scale (PANSS) for Schizophrenia        described in Kay et al., Schizophr. Bull. (1987) 13(2):261-276,        the contents of which are incorporated by reference in their        entirety. Negative symptoms include: blunted affect, emotional        withdrawal, poor rapport, passive/apathetic social withdrawal,        difficulty in abstract thinking, lack of spontaneity and flow of        conversation and stereotyped thinking. General psychopathology        symptoms include: somatic concern, anxiety, guilt feelings,        tension, mannerisms and posturing, depression, motor        retardation, uncooperativeness, unusual thought content,        disorientation, poor attention, lack of judgment and insight,        disturbance of volition, poor impulse control, preoccupation and        active social avoidance. Residual symptoms may also include        depression, cognitive impairment and sleep disorders (e.g.,        insomnia). Of these residual symptoms, the compounds of the        invention are particularly useful for the treatment of passive        social withdrawal, stereotyped thinking, somatic concerns,        anxiety, tension, active social avoidance and depression.        Therefore, the compounds of the present invention are        particularly useful in improving social integration and social        function in patients suffering from schizophrenia. Treatment of        these residual symptoms is also particularly effective in        schizophrenic patients also suffering from depression.    -   c. As used herein, the term “deuterated” refers to a compound        containing at least one C-D, N-D or O-D bond, wherein D is the        heavy hydrogen element deuterium, also known as ²H.

Unless otherwise indicated, the Compounds of the Invention, e.g.,Compounds of Formula I or I-B or any of 1-1.26, or any of formulae4.1-4.4 may exist in free or salt, e.g., as acid addition salts, form.An acid-addition salt of a compound of the invention which issufficiently basic, for example, an acid-addition salt with, forexample, an inorganic or organic acid, for example hydrochloric,hydrobromic, sulfuric, phosphoric, acid acetic, trifluoroacetic, citric,maleic acid, toluene sulfonic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, palmoic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isoethionic acid, and the like. In addition a saltof a compound of the invention which is sufficiently acidic is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically-acceptablecation, for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)-amine.In a particular embodiment, the salt of the Compounds of the Inventionis a toluenesulfonic acid addition salt. In another particularembodiment, the salt of the Compounds of the Invention is a fumaric acidaddition salt. In a particular embodiment, the salt of the Compounds ofthe Invention is a phosphoric acid addition salt.

The Compounds of the Invention are intended for use as pharmaceuticals,therefore pharmaceutically acceptable salts are preferred. Salts whichare unsuitable for pharmaceutical uses may be useful, for example, forthe isolation or purification of free Compounds of the Invention, andare therefore also included.

In some embodiments of the invention, Compounds of the Invention are notthemselves active moieties, but are rather pro-drugs of active moieties.The term “pro-drug” is a term recognized in the art, and it refers to adrug precursor prior to administration that generates or releases theactive metabolite in vivo following administration, via some chemical orphysiological process. In particular, Compounds of Formula I or I-B,wherein R¹ is H, or C₁₋₆ alkyl, or C₁₋₆ alkyl optionally substitutedwith D, are active moieties. In contrast, Compounds of Formula I or I-B,wherein R¹ is a pharmaceutically acceptable and physiologically labilemoiety, for example wherein R¹ is —C(O)—R² and wherein such group—C(O)—R² is a physiologically labile moiety, will have weak activity orno activity, but under physiological conditions will undergo hydrolysisto produce the Compounds of Formula I or I-B, wherein R¹ is H, and theother hydrolysis product which is not toxic at relevant concentrations(concentrations which would be provided by in vivo hydrolysis of adosage of the prodrug compound). For example, for a Compound of FormulaI or I-B wherein R¹ is —C(O)R², the hydrolysis products would be aCompound of Formula I wherein R1 is H, and the other hydrolysis productwould be a carboxylic acid of formula R²—C(O)—OH. Such physiologicallylabile moieties include, but are not limited to, carboxylic esters, forexample wherein R² is a C₁₋₂₁ alkyl group. Under some physiologicalconditions, Compounds of Formula I or I-B, wherein R¹ is C₁₋₆ alkyl(e.g., CH₃ or CD₃), may also under go in vivo conversion to the moreactive compound wherein R¹ is H, and therefore these compounds may beconsidered to be both active moieties and pro-drugs.

In a preferred embodiment of the invention, such pro-drug embodimentsare selected from the group in which R² is chosen to result in acompound that undergoes physiologic hydrolysis at a therapeuticallyeffective rate. One skilled in the art, will be able to select thesegroups to give Compounds of the Invention with a variety of physiologicrates of hydrolysis, solubility and membrane permeabilitycharacteristics, in order to achieve particular desired pharmacokineticor pharmacodynamics properties.

In another preferred embodiment, the groups from which R² may be chosenmay be based on the chemical, physical or toxicological properties ofthe by-product acids, of the formula R²—C—(O)—OH, which results fromhydrolysis of the pro-drug compounds. In some embodiments, the groupsmay be chosen so that hydrolysis of the pro-drug produces apharmacologically acceptable pro-moiety, e.g. one that is non-toxic andrapidly excreted and for the quantities generated in the course oftherapeutic treatment. Such commonly used pro-moieties include aceticacid, butyric acid, isobutyric acid, pivalic acid, and such naturallyoccurring fatty acids as stearic acid, lauric acid, palmitic acid,arachidonic acid, linoleic acid, linolenic acid and oleic acid.

The Compounds of the Invention may comprise one or more chiral carbonatoms. The compounds thus exist in individual isomeric, e.g.,enantiomeric or diastereomeric form or as mixtures of individual forms,e.g., racemic/diastereomeric mixtures. Any isomer may be present inwhich the asymmetric center is in the (R)-, (S)-, or(R,S)-configuration. The invention is to be understood as embracing bothindividual optically active isomers as well as mixtures (e.g.,racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds ofthe Invention may be a racemic mixture or it may be predominantly, e.g.,in pure, or substantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

Wherein X is —N(R⁵)—, and wherein R⁵ is CH₃ or CD₃, the Compounds of theInvention may further be metabolized in vivo to form the des-methylderivative (i.e., wherein X is —N(H)).

Alternatively and/or additionally, the Compounds of the Invention may beincluded as a depot formulation, e.g., by dispersing, dissolving orencapsulating the Compounds of the Invention in a polymeric matrix asdescribed in the second and third aspect, such that the Compound iscontinually released as the polymer degrades over time. The release ofthe Compounds of the Invention from the polymeric matrix provides forthe controlled- and/or delayed- and/or sustained-release of theCompounds, e.g., from the pharmaceutical depot composition, into asubject, for example a warm-blooded animal such as man, to which thepharmaceutical depot is administered. Thus, the pharmaceutical depotdelivers the Compounds of the Invention to the subject at concentrationseffective for treatment of the particular disease or medical conditionover a sustained period of time, e.g., 14-180 days, preferably about 30,about 60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of the Invention) may include apolyester of a hydroxy-fatty acid and derivatives thereof or otheragents such as polylactic acid, polyglycolic acid, polycitric acid,polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactonering opening polymer, lactic acid-glycolic acid copolymer,2-hydroxybutyric acid-glycolic acid copolymer, polylacticacid-polyethylene glycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (forexample poly(butyl 2-cyanoacrylate)), a polyalkylene oxalate (forexample polytrimethylene oxalate or polytetramethylene oxalate), apolyortho ester, a polycarbonate (for example polyethylene carbonate orpolyethylenepropylene carbonate), a polyortho-carbonate, a polyaminoacid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamicacid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and thelike, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly (lactic acid), or PLA). Most preferably, the polymeris the biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl-(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 daltons, preferably about 150,000 daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by any conventional method, or may becommercially available. For example, PLGA can be produced byring-opening polymerization with a suitable catalyst from cycliclactide, glycolide, etc. (see EP-0058481B2; Effects of polymerizationvariables on PLGA properties: molecular weight, composition and chainstructure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e. g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean3 of the hydroxy groups of the polyol being in the form of ester groups,which contain polylactide or co-polylactide chains. The branchedpolyesters, e. g., poly (d, 1-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The depot composition of the invention as hereinbefore described maycomprise the polymer in the form of microparticles or nanoparticles, orin a liquid form, with the Compounds of the Invention dispersed orencapsulated therein. “Microparticles” is meant solid particles thatcontain the Compounds of the Invention either in solution or in solidform wherein such compound is dispersed or dissolved within the polymerthat serves as the matrix of the particle. By an appropriate selectionof polymeric materials, a microparticle formulation can be made in whichthe resulting microparticles exhibit both diffusional release andbiodegradation release properties.

In a particular embodiment, the Compound of the Invention is formulatedinto microparticles of an appropriate size to allow slow releasekinetics after intramuscular injection.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the Compounds of the Invention and the polymer maybe dissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabilizer (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the Compounds of the Invention encapsulated therein.In the solvent extraction method, the Compounds of the Invention andpolymer may be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the Compounds of theInvention encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. No. 4,389,330 and U.S. Pat. No. 4,530,840,the contents of which are incorporated by reference.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the Compounds of the Invention and the polymeric matrixmaterial that can be employed in the practice of the present inventioninclude organic solvents, such as acetone; halogenated hydrocarbons,such as chloroform, methylene chloride, and the like; aromatichydrocarbon compounds; halogenated aromatic hydrocarbon compounds;cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and thelike. In one embodiment, the solvent for use in the practice of thepresent invention may be a mixture of benzyl alcohol and ethyl acetate.Further information for the preparation of microparticles useful for theinvention can be found in U.S. Patent Publication Number 2008/0069885,the contents of which are incorporated herein by reference in theirentirety.

The amount of the Compounds of the Invention incorporated in themicroparticles usually ranges from about 1 wt % to about 90 wt. %,preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight %is meant parts of the Compounds of the Invention per total weight ofmicroparticle.

The pharmaceutical depot may comprise a pharmaceutically-acceptablediluent or carrier, such as a water miscible diluent or carrier.

Details of Osmotic-controlled Release Oral delivery System compositionmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO2000/35419, the contents of each of which are incorporated by referencein their entirety.

A “therapeutically effective amount” is any amount of the Compounds ofthe invention (for example as contained in the pharmaceutical depot)which, when administered to a subject suffering from a disease ordisorder, is effective to cause a reduction, remission, or regression ofthe disease or disorder over the period of time as intended for thetreatment.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compounds of the Invention used, the mode ofadministration, and the therapy desired.

Compounds of the Invention may be administered by any satisfactoryroute, including orally, parenterally (intravenously, intramuscular orsubcutaneous) or transdermally, but are preferably administered orally.In certain embodiments, the Compounds of the Invention, e.g., in depotformulation, is preferably administered parenterally, e.g., byinjection.

In general, satisfactory results for Method I or any of formulae7.1-7.32 or Method Ip or use of the Compounds of the Invention ashereinbefore described, e.g. for the treatment of a combination ofdiseases such as a combination of at least depression, psychosis, e.g.,(1) psychosis, e.g., schizophrenia, in a patient suffering fromdepression; (2) depression in a patient suffering from psychosis, e.g.,schizophrenia; (3) mood disorders associated with psychosis, e.g.,schizophrenia, or Parkinson's disease; and (4) sleep disordersassociated with psychosis, e.g., schizophrenia, or Parkinson's disease,as set forth above are indicated to be obtained on oral administrationat dosages of the order from about 1 mg to 100 mg once daily, preferablyabout 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50mg, once daily, preferably via oral administration.

Satisfactory results for Method II or any of 8.1-8.15, Method II or useof the Compounds of the Invention as hereinbefore described, e.g. forthe treatment of sleep disorder alone or agitation, aggressivebehaviors, post-traumatic stress disorder or impulse control disorderalone, e.g., intermittent explosive disorder alone are indicated to beobtained on oral administration at dosages of the order from about 1mg-10 mg once daily, e.g., about 2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg,5 mg or 10 mg, of a Compound of the Invention, in free orpharmaceutically acceptable salt form, once daily, preferably via oraladministration.

Satisfactory results for Method I-A or any of 9.1-9.38 or Method I_(P)-Aare indicated to be obtained at less than 100 mg, preferably less than50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, lessthan 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactoryresults for Method II-A or any of 9.1-9.38 are indicated to be obtainedat less than 10 mg, e.g., less than 5 mg or, preferably less than 2.5mg.

For treatment of the disorders disclosed herein wherein the depotcomposition is used to achieve longer duration of action, the dosageswill be higher relative to the shorter action composition, e.g., higherthan 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greaterthan 1000 mg. In a particular embodiment, the dosage regimen for depotcomposition includes an initial oral immediate dose along with depotrelease so as to provide a steady-state blood level of the drug.Duration of action of the Compounds of the Invention may be controlledby manipulation of the polymer composition, i.e., the polymer:drug ratioand microparticle size. Wherein the composition of the invention is adepot composition, administration by injection is preferred.

The pharmaceutically acceptable salts of the Compounds of the Inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free base forms of these compounds witha stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients (an example include,but is not limited to sesame oil) and techniques known in the galenicart. Thus oral dosage forms may include tablets, capsules, solutions,suspensions and the like.

All references herein to dosage, dosage rate or therapeutically effectamount of a Compound or Composition of the Invention refers to theequivalent free-base or pharmaceutically acceptable salt form of thenon-pro-drug moiety or the in the dosage, or in other words, theactive-moiety (the Compound of the Invention, wherein R¹ is H or C₁₋₆alkyl), of the compound or composition described.

Methods of Making the Compounds of the Invention:

The intermediates of the Compounds of the Invention may be prepared asdescribed in WO PCT/US08/03340 (WO 2008/112280); U.S. application Ser.No. 10/786,935; U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, the contents ofwhich are incorporated by reference in their entirety. Salts of theCompounds of the Invention may also be prepared as similarly describedin U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282;U.S. RE39680; U.S. RE39679; and WO 2009/114181, the contents of each ofwhich are incorporated by reference in their entirety. All substituentsX, R¹, R², R³, R⁴, R⁵ and R⁶ appearing in the structures and formulas ofthe Examples below are as defined for Formula I and I-B hereinbefore.

Isolation or purification of the diastereomers of the Compounds of theInvention may be achieved by conventional methods known in the art,e.g., column purification, preparative thin layer chromatography,preparative HPLC, crystallization, trituration, simulated moving bedsand the like.

The Compounds of Formula I or I-B can be prepared by standard methodsknown to those skilled in the art. U.S. Pat. No. 8,309,722, which isincorporated by reference in its entirety, discloses the synthesis ofthe Compound of Formula Q, and all of the intermediates therefor:

The Compounds of the Invention are synthesized from the relatedCompounds of the Formula Q-B, wherein in X, R³ and R⁴ are as defined forFormula I or I-B, which are prepared in like manner to the Compounds ofFormula Q, using, for example, the intermediate Compounds B and D, asshown in the examples below.

For example, Compound B may be prepared from Compound A (disclosed inthe U.S. Pat. No. 8,309,722) by reacting with d3-iodomethane in thepresence of a base, such as potassium carbonate or sodium hydride, in asuitable solvent, such as acetone or dimethylformamide. Following theprocedures of U.S. Pat. No. 8,309,722 and those herein, Compound B canthen be converted to a Compound of Formula I or I-B, wherein X is N(R⁵)and R⁵ is CD3. The reaction may be summarized in the reaction schemebelow:

For example, Compound D may be prepared from a Compound of Formula C(disclosed in the U.S. Pat. No. 8,309,722, and herein) by reacting withd3-borane THF complex, in a suitable solvent, such as tetrahydrofuran.Following the procedures of U.S. Pat. No. 8,309,722 and those herein,Compound D can then be converted a Compound of Formula I or I-B, whereinR³ and R⁴ are D. The reaction may be summarized in the reaction schemebelow:

The Compounds of Formula I can be prepared by standard methods known tothose skilled in the art. For example, the Compound of Formula I or I-B,wherein R1 is H, and wherein X is as defined in Formula I or I-B, e.g. Xis, for example, N(CH₃), may be prepared by reacting Compound E witheither sodium borodeuteride or lithium aluminum deuteride in an etherealsolvent such as tetrahydrofuran, optionally containing a deuteratedprotic co-solvent such as methyl alcohol-d (CH₃OD). The reaction may besummarized in the reaction scheme below:

A Compound of Formula I or I-B, wherein R¹ is C₁₋₆ alkyl may be preparedby reacting Compound F with R¹—OH and BF₃-OEt₂. The reaction may besummarized in the reaction scheme below:

A Compound of Formula I or I-B wherein R¹ is —C(O)—R², and wherein R²is, e.g. ethyl, may be prepared by reacting Compound F with, e.g.propanoyl chloride in a solvent such as dichloromethane, in the presenceof a base such as triethylamine and N,N-dimethyl-4-aminopyridine (DMAP).The reaction may be summarized in the reaction scheme below:

Similar compounds of Formula I or I-B wherein R¹ is —C(O)—R², andwherein R² is C₁₋₂₁ alkyl, optionally substituted with D, may beprepared in an analogous manner.

1. A compound of formula I:

wherein: X is N(H), N(R⁵) or 0; R⁵ is C₁₋₆ alkyl, optionally substitutedwith D; R³ and R⁴ are each independently H or D; R⁶ is H or D; R¹ is H,or C₁₋₆ alkyl, optionally substituted with D, or a pharmaceuticallyacceptable and physiologically labile moiety, wherein D is deuterium,and provided that at least one of R¹, R², R³, R⁴, R⁵, or R⁶ includes atleast one D; in free or salt form.
 2. The compound according to claim 1,wherein said compound is a compound of Formula I-B:

wherein: X is N(H), N(R⁵) or 0; R⁵ is C₁₋₆ alkyl; R¹ is H, or C₁₋₆alkyl, or a pharmaceutically acceptable and physiologically labilemoiety, and wherein D is deuterium.
 3. The compound according to claim1, wherein R¹ is H.
 4. The compound according to claim 1, wherein R¹ isC₁₋₆ alkyl.
 5. The compound according to claim 1, wherein R¹ is C₁₋₆alkyl optionally substituted with D.
 6. The compound according to claim1, wherein R¹ is CH₃.
 7. The compound according to claim 1 wherein R¹ isCD₃.
 8. The compound according to claim 1, wherein R¹ is apharmaceutically acceptable and physiologically labile moiety.
 9. Thecompound according to claim 1, wherein R¹ is —C(O)—R², and wherein R² isC₁₋₂₁ alkyl.
 10. The compound according to claim 1, wherein R¹ is—C(O)—R², and wherein R² is C₁₋₁₅ alkyl.
 11. The compound according toclaim 1, wherein R¹ is —C(O)—R², and wherein R² is C₁₋₉ alkyl.
 12. Thecompound according to claim 1, wherein R¹ is —C(O)—R², and wherein R² ismethyl, ethyl or propyl.
 13. The compound according to claim 1, whereinR¹ is —C(O)—R², and wherein R² is methyl.
 14. The compound according toclaim 1, wherein X is N(H), N(R⁵) or O.
 15. The compound according toclaim 1, wherein X is O.
 16. The compound according to claim 1, whereinX is N(H).
 17. The compound according to claim 1, wherein X is N(R⁵),and wherein R⁵ is C₁₋₄ alkyl.
 18. The compound according to claim 1,wherein X is N(R⁵), and wherein R⁵ is CH₃.
 19. The compound according toclaim 1, wherein X is N(R⁵), and wherein R⁵ is CD₃.
 20. The compoundaccording to claim 1, wherein R³ is D.
 21. The compound according toclaim 1, wherein R⁴ is D.
 22. The compound according to claim 1, whereinR³ and R⁴ are D.
 23. The compound according to claim 1, wherein X isN(R⁵), and R⁵ is CD₃ and R³ and R⁴ are both D.
 24. The compoundaccording to claim 1, wherein the Compound is:


25. The compound according to claim 1, wherein the Compound is:


26. The compound according to claim 1, wherein the Compound is:


27. The compound according to claim 1, wherein said compound is in saltform.
 28. The compound according to claim 27, wherein the salt isselected from a group consisting of toluenesulfonic, fumaric andphosphoric acid addition salt.
 29. A pharmaceutical compositioncomprising a compound according to claim 1, in free or pharmaceuticallyacceptable salt form, in combination or association with apharmaceutically acceptable diluent or carrier.
 30. A method for thetreatment or prophylaxis of a central nervous system disorder comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition according to claim
 29. 31. Themethod according to claim 30, wherein said disorder is selected from agroup consisting of obesity, anxiety, depression, psychosis,schizophrenia, sleep disorders, sexual disorders, migraine, conditionsassociated with cephalic pain, social phobias, agitation, agitation indementia, agitation in autism and related autistic disorders,gastrointestinal disorders such as dysfunction of the gastrointestinaltract motility, post-traumatic stress disorder, impulse controldisorders, and intermittent explosive disorder.
 32. The method accordingto claim 30, wherein said disorder is one or more disorders associatedwith dementia, selected from disorders associated with mild cognitionimpairment and dementing illnesses including senile dementia,Alzheimer's disease, Pick's disease, fronto-temporal dementia,parasupranuclear palsy, dementia with Lewy bodies, vascular dementia,Huntington's disease, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis, Down syndrome, elderly depression,Wernicke-Korsakoff s syndrome, cortico-basal degenerations and priondisease, autism and attention deficit hyperactivity disorder.
 33. Themethod according to claim 30, wherein said disorder is a disorderinvolving one of the serotonin 5-HT_(2A), dopamine D2 and/or serotoninreuptake transporter (SERT) pathways.
 34. The method according to claim30, wherein the central nervous system disorder is residual symptoms ofpsychosis, in a patient suffering from schizophrenia, delusionaldisorder, major depression with psychosis, bipolar disorder withpsychotic symptoms, brief psychotic disorder, schizophreniform disorder,schizoaffective disorder, or psychosis caused by a medical condition orsubstance use.
 35. The method according to claim 34, wherein saidresidual phase symptoms are selected from negative symptoms such asblunted affect, emotional withdrawal, poor rapport, passive or apatheticsocial withdrawal, difficulty in abstract thinking, lack of spontaneityand flow of conversation and stereotyped thinking; generalpsychopathology symptoms such as somatic concern, anxiety, guiltfeelings, tension, mannerisms and posturing, depression, motorretardation, uncooperativeness, unusual thought content, disorientation,poor attention, lack of judgment and insight, disturbance of volition,poor impulse control, preoccupation and active social avoidance;cognitive impairment and sleep disorders.
 36. The method according toclaim 30, further comprising the administration of one or more othertherapeutic agents such as an additional antipsychotic agents and/oranti-depressive agents and/or hypnotic agents.
 37. The method of claim36, wherein the one or more other therapeutic agents are selected fromanti-depressive agents such as compounds that modulate GABA activity, aGABA-B agonist, a 5-HT modulator, a melatonin agonist, an ion channelmodulator (e.g., blocker) a serotonin-2 antagonist/reuptake inhibitor(SARIs), an orexin receptor antagonist, an H3 agonist, a noradrenergicantagonist, a galanin agonist, a CRH antagonist, human growth hormone, agrowth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1drug; and antipsychotic agents, in free or pharmaceutically acceptablesalt form.
 38. The method according to claim 36, wherein the one or moreother therapeutic agents are antipsychotic agents selected fromchlorpromazine, haloperidol, droperidol, fluphenazine, loxapine,mesoridazine molindone, perphenazine, pimozide, prochlorperazinepromazine, thioridazine, thiothixene, trifluoperazine, clozapine,aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone,paliperidone, asenapine, lurasidone, iloperidone, cariprazine,amisulpride, zotepine, sertindole, in free or pharmaceuticallyacceptable salt form.
 39. The method of according to claim 36, whereinthe one or more other therapeutic agents are anti-depressive agentsselected from one or more of amitriptyline, amoxapine, bupropion,citalopram, clomipramine, desipramine, doxepin, duloxetine,escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid,maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,phenelazine sulfate, protriptyline, sertraline, tranylcypromine,trazodone, trimipramine, and venlafaxine.
 40. The method according toclaim 36 wherein the one or more other therapeutic agents areanti-depressive agent selected from selective serotonin reuptakeinhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors(SNRIs), and tricyclic antidepressants.
 41. The method of claim 40,wherein the anti-depressive agent is a SSRI.